One of the major protective functions of the skin is derived from its uniquely low permeability. Diffusion through intact healthy epidermis is much slower than through connective tissue or through capillary walls. That part of the epidermis which is responsible for the major portion of its protective capacity is the stratum corneum, the thin sheath of dried, keratinized cells which comprises the outermost layer. Much of the basic physical chemistry of this tissue relevant to its transport behavior is still unknown. Our broad research objective is ultimately to understand how the skin functions so effectively as a "barrier" and how this effectiveness may be destroyed or modified by environmental influences and/or by disease. Our method of approach is a systematic study of the physical chemistry and the transport properties of human epidermis and the stratum corneum in particular. The measurement in vitro of the comparative rates of diffusion of homologous series of non-electrolytes, ions and gases through intact and variously treated tissue is an essential part of the work. Equally important are corresponding measurements of the physical structure of the tissue, e.g., X-ray diffraction and berefringence measurements of the protein and lipid conformation; stress-strain measurements of dry, wet and solvent treated tissue and ultrastructural studies (electron microscopy and scanning e.m.). The effect of hydration or dehydration, solvent damage, solute solubility, temperature induced ultrastructural changes and the role of skin lipids on the performance of the skin as a protective "barrier" can be accurately and meaningfully studied in this way. Greater understanding of the principles which govern skin permeability and more knowledge of those factors which can accelerate or retard the penetration of substances should prove valuable both in the area of environmental health and in cutaneous disease.